Evidence for monoaminergic involvement in triadimefon-induced hyperactivity

Triadimefon is a triazole fungicide that produces hyperactivity in both mice and rats similar to that seen following administration of compounds with catecholaminergic activity (e.g., d-amphetamine). To determine whether the triadimefon-induced hyperactivity is due to an action on CNS catecholaminergic systems, we evaluated the effects of combined treatment of triadimefon with either the tyrosine hydroxlase inhibitor d,l--methyl-p-tyrosine methyl ester HCl (MPT) or the amine depletor reserpine. Adult male Long-Evans hooded rats, approximately 70 days of age were used. Dosage-effect functions were determined for MPT (0–200 mg/kg IP), reserpine (0–2.5 mg/kg IP), d-amphetamine (0–3 mg/kg IP), and methylphenidate (0–40 mg/kg IP). Motor activity was measured as photocell interruptions in figure-eight mazes. The interaction between triadimefon and MPT was determined with the following groups: 1) vehicle control; 2) 200 mg/kg triadimefon PO; 3) 100 mg/kg MPT; and 4) both MPT and triadimefon. A similar design was used to determine the interaction between triadimefon and reserpine (0.62 mg/kg), MPT and d-amphetamine (1.5 mg/kg), and reserpine and methylphenidate (5.0 mg/kg). In the first experiment MPT did not block the increased motor activity produced by triadimefon (i.e., both triadimefon alone and MPT in combination with triadimefon produced significant increases in motor activity). MPT did, however, block d-amphetamine-induced hyperactivity. Since MPT did not antagonize the effect of triadimefon, these data suggest that increased motor activity produced by triadimefon is not mediated through release of newly synthesized catecholamines. In contrast, pretreatment with reserpine blocked the hyperactivity induced by both triadimefon and methylphenidate, which suggests that triadimefon-induced hyperactivity may be due to an interaction with CNS catecholamines stored in reserpine-sensitive pools.The research described in this article has been reviewed by the Health Effects Research Laboratory, US Environmental Protection Agency, and approved for publication. Approval does not signify that the contents necessarily reflect the views and policies of the Agency nor does mention of trade names or commercial products constitute endorsement or recommendation for use. Presented in part at the Annual Meeting of the Society for Neuroscience, New Orleans, LA, November, 1987     

Discriminative stimulus properties of triadimefon: Comparison with methylphenidate

Two groups of rats (N=4 each) were trained to discriminate either triadimefon (40 mg/kg) or methylphenidate (4 mg/kg) from saline in a two-lever, milk-reinforced drug discrimination paradigm. Dose-response functions were determined during 5-min extinction sessions. Both agents produced a dose-related increase in the percentage of responses that occurred on the drug lever. In the substitution phase of the study, rats trained to discriminate triadimefon were tested with methylphenidate and rats trained to discriminate methylphenidate were tested with triadimefon. Triadimefon substituted completely for methylphenidate and methylphenidate substituted completely for triadimefon. These results indicate that triadimefon can function as a discriminative stimulus and that it shares discriminative stimulus properties with methylphenidate.     

Effects of triadimefon on a multiple schedule of fixed-interval performance: Comparison with methylphenidate, d-amphetamine and chlorpromazine

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10–170 mg/kg, IP) and of methylphenidate (1–17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3–3.0 mg/kg, IP) and chlorpromazine (0.5–2.0 mg/kg, IP). Response rates were increased d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact. Although triadimefon did not closely resemble any of the comparison drugs, it had opposite effects on response rates from chlorpromazine in both components of the schedule and resembled d-amphetamine in its effects on FI 1-min response rates. The rate-increasing effects frequently obtained with psychomotor stimulants were more evident for triadimefon than for either methylphenidate or d-amphetamine.     

Interactions of paraquat and triadimefon: behavioral and neurochemical effects

Triadimefon (TDF), a triazole fungicide, and paraquat (PQ), a non-selective herbicide/dessicant, are both known to adversely impact brain dopaminergic function and are used in overlapping geographical areas of the US. Since "real world" situations indicate humans are exposed to a diverse mixture of chemicals, this study hypothesized that combined exposures to PQ+TDF could produce interactive effects by simultaneously attacking multiple target sites of dopamine systems. Thus, 10 mg/kg PQ (PQ10) and 25 or 50 mg/kg TDF (TDF25 and 50, respectively) were administered i.p. to male C57BL/6 mice, 2x per week for 12 weeks, either alone or in combination. Acutely, TDF50 increased horizontal and vertical activity with increased vertical activity still occurring 24h later, indicative of sustained behavioral sensitization. Acutely, PQ decreased horizontal but not vertical activity with a lack of residual effects at 24h. PQ prevented the increased levels of activity associated with TDF50. These interactions differed for horizontal and vertical activity, indicating their differential neurochemical mediation, and suggesting that they did not arise from simple additivity of PQ and TDF effects. Nor could the interactive effects be readily ascribed to corresponding neurochemical interactions, since all treatments generally increased levels of DA and metabolites acutely in striatum and were associated with general reductions in levels of DA and metabolites and turnover in striatum and frontal cortex 7 days after the final treatment. Thus, TDF and PQ both separately and through interactions may serve as environmental risk factors through different mechanisms for dopaminergically-mediated behavioral dysfunctions.     

心理干预辅助曲唑酮治疗COPD抑郁状态的观察

目的观察心理干预辅助曲唑酮治疗慢性阻塞性肺疾病抑郁状态的效果。方法选择合并抑郁状态的慢性阻塞性肺疾病急性加重期（AECOPD）患者90例,随机分为Ⅰ组、Ⅱ组、Ⅲ组,Ⅱ组在Ⅰ组治疗基础上予以心理干预,Ⅲ组在Ⅱ组治疗基础上加用口服曲唑酮片。于治疗前、治疗1周、治疗4周采用问卷调查形式进行Zung抑郁自测量表（SDS）评分。结果与Ⅰ组比较,Ⅱ组治疗后1周有显著性差异（P〈0.01）,Ⅲ组在治疗后1周和4周有显著性差异（P〈0.01）。结论心理干预辅助曲唑酮对于改善AECOPD患者抑郁状态具有起效快、作用时间长的特点,但其长期效果需进一步临床观察。     

Development and application of a physiologically based pharmacokinetic model for triadimefon and its metabolite triadimenol in rats and humans

A physiologically based pharmacokinetic (PBPK) model was developed for the conazole fungicide triadimefon and its primary metabolite, triadimenol. Rat tissue:blood partition coefficients and metabolic constants were measured in vitro for both compounds. Pharmacokinetic data for parent and metabolite were collected from several tissues after intravenous administration of triadimefon to male Sprague-Dawley rats. The model adequately simulated peak blood and tissue concentrations but predicted more rapid clearance of both triadimefon and triadimenol from blood and tissues. Reverse metabolism of triadimenol to triadimefon in the liver was explored as a possible explanation of this slow clearance, with significant improvement in model prediction. The amended model was extrapolated to humans using in vitro metabolic constants measured in human hepatic microsomes. Human equivalent doses (HEDs) were calculated for a rat no observable adverse effect level (NOAEL) dose of 3.4 mg/kg/day using area under the concentration curve (AUC) in brain and blood for triadimefon and triadimenol as dosimetrics. All dosimetric-based HEDs were 25-30 fold above the human oral reference dose of 0.03 mg triadimefon/kg/day, but did not account for intra-human variability or pharmacodynamic differences. Ultimately, derivations of this model will be able to better predict the exposure profile of these and other conazole fungicides in humans.     

Toxicogenomic effects common to triazole antifungals and conserved between rats and humans

The triazole antifungals myclobutanil, propiconazole and triadimefon cause varying degrees of hepatic toxicity and disrupt steroid hormone homeostasis in rodent in vivo models. To identify biological pathways consistently modulated across multiple timepoints and various study designs, gene expression profiling was conducted on rat livers from three separate studies with triazole treatment groups ranging from 6 h after a single oral gavage exposure, to prenatal to adult exposures via feed. To explore conservation of responses across species, gene expression from the rat liver studies were compared to in vitro data from rat and human primary hepatocytes exposed to the triazoles. Toxicogenomic data on triazoles from 33 different treatment groups and 135 samples (microarrays) identified thousands of probe sets and dozens of pathways differentially expressed across time, dose, and species — many of these were common to all three triazoles, or conserved between rodents and humans. Common and conserved pathways included androgen and estrogen metabolism, xenobiotic metabolism signaling through CAR and PXR, and CYP mediated metabolism. Differentially expressed genes included the Phase I xenobiotic, fatty acid, sterol and steroid metabolism genes Cyp2b2 and CYP2B6, Cyp3a1 and CYP3A4, and Cyp4a22 and CYP4A11; Phase II conjugation enzyme genes Ugt1a1 and UGT1A1; and Phase III ABC transporter genes Abcb1 and ABCB1. Gene expression changes caused by all three triazoles in liver and hepatocytes were concentrated in biological pathways regulating lipid, sterol and steroid homeostasis, identifying a potential common mode of action conserved between rodents and humans. Modulation of hepatic sterol and steroid metabolism is a plausible mode of action for changes in serum testosterone and adverse reproductive outcomes observed in rat studies, and may be relevant to human risk assessment.     

Gender and species differences in triadimefon metabolism by rodent hepatic microsomes

Understanding the potential differences in metabolic capacity and kinetics between various common laboratory species as well as between genders is an important facet of chemical risk assessment that is often overlooked, particularly for chemicals which undergo non-cytochrome P450 mediated metabolism. The use of physiologically based pharmacokinetic (PBPK) models to better describe chemical exposure is made more powerful by incorporation of high quality in vitro kinetic data. To this end, metabolism of the conazole fungicide triadimefon was studied in hepatic microsomes of both genders of SD rats and CD-1 mice. Triadimefon depletion and triadimenol formation were measured in each type of microsomes. Michaelis–Menten regressions were applied to metabolic data and V_MAX and the Michaelis constant (K_M) values calculated. Male SD rats metabolized triadimefon more rapidly than female SD rats or either gender of CD-1 mouse. K_M values were in the micromolar range, indicating the possibility of competitive inhibition with endogenous substrates. Intrinsic clearances derived from kinetic parameters indicate that triadimefon metabolism is blood-flow limited in all organisms studied with the possible exception of female rat. The in vitro half-life method was investigated as a less resource intensive method for the derivation of intrinsic clearance, and was found to be useful as a complement to the traditional Michaelis–Menten approach.     

Effects of dexfenfluramine and opioid peptides, alone or in combination, on food intake and brain serotonin turnover in rats.

Triadimefon is a fungicide that has recently been shown to increase motor activity and rates of schedule-controlled responding. These findings indicate that triadimefon resembles psychomotor stimulants and in this respect is a unique pesticide. The present experiment was designed to evaluate triadimefon's effects on performance maintained by a multiple schedule of reinforcement and to compare triadimefon to known psychomotor stimulants. Four rats were trained to perform under a mult FI 1-min FI 5-min schedule of milk reinforcement. They then received a series of dosages of triadimefon (10–170 mg/kg, IP) and of methylphenidate (1–17.3 mg/kg, IP) in a counterbalanced order. Triadimefon increased response rates in both the FI 1-min and FI 5-min components. Methylphenidate did not consistently alter response rates in either component. Temporal patterns of responding were disrupted much more in the FI 5-min component than in the FI 1-min component by both triadimefon and methylphenidate. Performances were then evaluated following a series of dosages of d-amphetamine (0.3–3.0 mg/kg, IP) and chlorpromazine (0.5–2.0 mg/kg, IP). Response rates were increased d-amphetamine in the FI 1-min component but not in the FI 5-min component. Like triadimefon and methylphenidate, d-amphetamine produced a greater disruption of response patterning in FI 5-min than in FI 1-min. Only chlorpromazine decreased response rates in both components. Chlorpromazine also disrupted FI 5-min response patterning, but left FI 1-min patterning intact. Although triadimefon did not closely resemble any of the comparison drugs, it had opposite effects on response rates from chlorpromazine in both components of the schedule and resembled d-amphetamine in its effects on FI 1-min response rates. The rate-increasing effects frequently obtained with psychomotor stimulants were more evident for triadimefon than for either methylphenidate or d-amphetamine.